Submissions for variant NM_000059.4(BRCA2):c.5791C>T (p.Gln1931Ter)

dbSNP: rs80358807

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000077361	SCV000300934	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2016-09-08	reviewed by expert panel	curation	Variant allele predicted to encode a truncated non-functional protein.
Ambry Genetics	RCV000131105	SCV000186035	pathogenic	Hereditary cancer-predisposing syndrome	2019-07-09	criteria provided, single submitter	clinical testing	The p.Q1931* pathogenic mutation (also known as c.5791C>T), located in coding exon 10 of the BRCA2 gene, results from a C to T substitution at nucleotide position 5791. This changes the amino acid from a glutamine to a stop codon within coding exon 10. This mutation is located in the ovarian cancer cluster region of BRCA2 and has previously been reported in a woman diagnosed with ovarian cancer (Pal T et al. Cancer. 2005 Dec 15;104(12):2807-16). This alteration has been reported in a cohort of Korean breast cancer patients (Park B et al. Breast Cancer Res. Treat. 2017 May;163:139-150) and a large cohort of Chinese breast and/or ovarian cancer patients (Bhaskaran SP et al. Int. J. Cancer. 2019 Aug;145:962-973). This alteration was also identified in a large, worldwide study of BRCA1/2 mutation positive families (Rebbeck TR et al. Hum. Mutat. 2018 05;39:593-620). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000077361	SCV000327283	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-10-02	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000763323	SCV000894000	pathogenic	Familial cancer of breast; Breast-ovarian cancer, familial, susceptibility to, 2; Fanconi anemia complementation group D1; Medulloblastoma; Wilms tumor 1; Malignant tumor of prostate; Pancreatic cancer, susceptibility to, 2; Glioma susceptibility 3	2018-10-31	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001852944	SCV002139710	pathogenic	Hereditary breast ovarian cancer syndrome	2023-11-06	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gln1931*) in the BRCA2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in BRCA2 are known to be pathogenic (PMID: 20104584). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with breast and/or ovarian cancer (PMID: 16284991, 28205045, 28692638, 29446198). This variant is also known as 6019C>T. ClinVar contains an entry for this variant (Variation ID: 51939). For these reasons, this variant has been classified as Pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV000131105	SCV004362126	pathogenic	Hereditary cancer-predisposing syndrome	2022-03-01	criteria provided, single submitter	clinical testing	This variant changes 1 nucleotide in exon 11 of the BRCA2 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in 1 individual affected with breast cancer and 1 individual affected with ovarian cancer (PMID: 16284991, 28205045) and has been identified in 2 families among the CIMBA participants (PMID: 29446198). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of BRCA2 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001852944	SCV004804110	pathogenic	Hereditary breast ovarian cancer syndrome	2024-01-04	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.5791C>T (p.Gln1931X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant was absent in 250660 control chromosomes. c.5791C>T has been reported in the literature in a setting of multi-gene testing in at least one individual affected with breast cancer (e.g. Subasioglu_2023). These data suggest the variant is likely associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 36605468). Five submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Juno Genomics, Hangzhou Juno Genomics, Inc	RCV000077361	SCV005416602	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2		criteria provided, single submitter	clinical testing	PM2_Supporting+PVS1+PS4_Supporting
Sharing Clinical Reports Project (SCRP)	RCV000077361	SCV000109158	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2012-08-02	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000077361	SCV000146700	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2003-12-23	no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV001723634	SCV001953750	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001723634	SCV001969181	pathogenic	not provided		no assertion criteria provided	clinical testing